Denali Therapeutics Announces U.S. FDA Breakthrough Therapy Designation Granted to Tividenofusp Alfa for the Treatment of Hunter Syndrome (MPS II)

Rhea-AI Summary

Denali Therapeutics (NASDAQ: DNLI) announced that the FDA has granted Breakthrough Therapy Designation for tividenofusp alfa (DNL310) for treating Hunter syndrome (MPS II). This adds to previously received Fast Track, Orphan Drug, and Rare Pediatric Disease designations.

The company plans to submit a Biologics License Application (BLA) in early 2025 under the accelerated approval pathway. The designation was supported by promising results from an open-label Phase 1/2 study showing positive effects on surrogate endpoints and early signs of improved clinical outcomes.

Breakthrough Therapy Designation expedites development and review of therapies for serious conditions, providing more intensive FDA guidance, senior reviewer involvement, and eligibility for rolling and priority review. This designation requires preliminary clinical evidence indicating substantial improvement over existing therapies.

Positive

• Received FDA Breakthrough Therapy Designation, adding to three other special designations
• Eligibility for expedited development, rolling review, and priority review
• Promising Phase 1/2 clinical trial results
• BLA submission planned for early 2025 under accelerated approval pathway

Negative

• Product still requires full FDA approval
• market size due to rare disease indication

Insights

Regulatory Affairs Expert

The FDA's Breakthrough Therapy Designation for tividenofusp alfa represents a major regulatory milestone for Denali Therapeutics. This designation, combined with previously granted Fast Track, Orphan Drug and Rare Pediatric Disease designations, creates a powerful regulatory package that significantly expedites the development pathway. The planned BLA submission in early 2025 under accelerated approval indicates strong clinical evidence and potential market entry within 6-8 months of filing. The designation typically reduces approval timeline by 4-6 months and provides enhanced FDA support, including senior reviewer involvement and rolling review eligibility. For rare diseases like Hunter syndrome, this regulatory advantage is particularly valuable as it can accelerate market access by up to 1-2 years compared to standard review pathways.

Biotech Investment Analyst

This regulatory advancement substantially derisks Denali's lead program and strengthens its market position. With a $3B market cap, successful commercialization of tividenofusp alfa could drive significant value creation, considering the Hunter syndrome market opportunity. The Enzyme TransportVehicle™ platform validation through this program could unlock additional value across Denali's pipeline. Historical data shows breakthrough designations correlate with 85% approval rates, significantly higher than the industry average of 50%. For investors, this news reduces regulatory risk and potentially accelerates revenue timeline, which could catalyze multiple expansion. The broader implications for Denali's platform technology could position the company as a leader in treating CNS-related rare diseases.

Medical Research Analyst

The clinical significance of tividenofusp alfa lies in its unique ability to cross the blood-brain barrier, addressing both central nervous system and peripheral manifestations of Hunter syndrome - a critical unmet need. Current standard of care, enzyme replacement therapy, cannot effectively reach the brain. The positive Phase 1/2 data referenced suggests promising efficacy on surrogate endpoints, which is particularly important for rare disease drug development. Given Hunter syndrome's progressive nature and treatment options, tividenofusp alfa's potential to modify disease progression represents a paradigm shift in treatment approach. The therapeutic's dual-action mechanism (brain and body) could establish a new standard of care in the MPS II treatment landscape.

Denali expects to submit a Biologics License Application for tividenofusp alfa in early 2025 for regulatory review under the accelerated approval pathway

SOUTH SAN FRANCISCO, Calif., Jan. 08, 2025 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ: DNLI), today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for tividenofusp alfa (DNL310) for the treatment of individuals with Hunter syndrome (MPS II). This designation is in addition to Fast Track Designation, Orphan Drug Designation, and Rare Pediatric Disease Designation, all previously granted by the FDA for tividenofusp alfa in Hunter syndrome. Denali expects to submit a Biologics License Application (BLA) for tividenofusp alfa in early 2025 for regulatory review under the accelerated approval pathway.

“FDA Breakthrough Therapy Designation is another significant achievement in the development of tividenofusp alfa, our first Enzyme TransportVehicle™ program, uniquely designed to optimize enzyme delivery to both brain and body, addressing the full spectrum of Hunter syndrome, a progressive and devastating disease,” said Carole Ho, M.D., Chief Medical Officer of Denali Therapeutics. “Data from the open-label Phase 1/2 study have shown promising results, with positive effects on evidence-based surrogate endpoints and early signs of improved clinical outcomes in participants with Hunter syndrome. We are grateful to the FDA for recognizing the potential of tividenofusp alfa as a meaningful treatment option for individuals with Hunter syndrome. We look forward to continued collaboration with the FDA to bring an effective therapy to the Hunter syndrome community as soon as possible.”

Breakthrough Therapy Designation is intended to expedite the development and review of therapeutic candidates that are under investigation for the treatment of serious or life-threatening conditions. Breakthrough Therapy Designation requires preliminary clinical evidence suggesting a candidate may provide substantial improvement over available therapy on at least one clinically significant endpoint. This designation provides Denali with more intensive FDA guidance, including involvement of senior reviewers, and eligibility for rolling review and priority review of the marketing application.

About Hunter Syndrome (MPS II)

Hunter syndrome (MPS II) is a rare genetic disease that affects over 2,000 individuals in commercially accessible geographies, primarily males, and leads to physical, cognitive, and behavioral symptoms. Hunter syndrome is caused by mutations in the iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of the IDS enzyme. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of glycosaminoglycans (GAGs) in lysosomes — the part of the cell that breaks down materials including GAGs. The current standard of care, enzyme replacement therapy, partially treats physical symptoms but does not cross the blood-brain barrier, and as a result, cognitive and behavioral symptoms experienced by the majority of individuals with Hunter syndrome are not addressed. Therapies that address the range of behavioral, cognitive, and physical manifestations of the disease are recognized as an unmet need for the Hunter syndrome community.¹

About Tividenofusp Alfa

Tividenofusp alfa (or DNL310) is composed of iduronate 2-sulfatase (IDS) fused to Denali’s proprietary Enzyme TransportVehicle™ (ETV), which is engineered for active transport into the brain and broad delivery throughout the body with the goal of addressing behavioral, cognitive, and physical symptoms of Hunter syndrome (MPS II). In 2021, the U.S. Food and Drug Administration granted Fast Track designation to tividenofusp alfa for the treatment of patients with Hunter syndrome (MPS II). In 2022, the European Medicines Agency granted tividenofusp alfa Priority Medicines designation. Denali has announced the outcome of a meeting with the FDA providing a path to filing a biologics license application (BLA) for accelerated approval and subsequent conversion to full approval for the treatment of Hunter syndrome (MPS II). Tividenofusp alfa is an investigational drug and its safety and efficacy profile has not yet been established. Tividenofusp alfa has not been approved by any Health Authority for any use.

About Denali Therapeutics

Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding Denali's plans, timelines, and expectations related to tividenofusp alfa (DNL310), including interactions with the FDA, the timing of planned regulatory filings, and the timing, pathway, and likelihood of regulatory approval; Denali’s overall development plans; and statements made by Denali’s Chief Medical Officer. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to: Denali’s dependence on successful development of its BBB platform technology and TV-enabled product candidates; Denali’s ability to initiate and enroll patients in its current and future clinical trials; Denali’s ability to conduct or complete clinical trials on expected timelines; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; the potential for clinical trial results to differ from preclinical, early clinical, preliminary or expected results; the risk of significant adverse events, toxicities, or other undesirable side effects; the risk that results from early clinical biomarker studies will not translate to clinical benefit in late clinical studies; the risk that product candidates may not receive regulatory approval necessary to be commercialized; developments relating to Denali’s competitors and its industry, including competing product candidates and therapies; Denali’s ability to obtain, maintain, or protect intellectual property rights; and other risks and uncertainties. In light of these risks, uncertainties, and assumptions, the forward-looking statements in this press release are inherently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Accordingly, you should not rely upon forward-looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali’s Annual and Quarterly Reports filed on Forms 10-K and 10-Q filed with the Securities and Exchange Commission (SEC) on February 28, 2024, and November 6, 2024, respectively, and Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward-looking statements, to conform these statements to actual results or to make changes in Denali’s expectations, except as required by law.

References

1. Muenzer, J., et al. Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses. Mol Genet Metab. 2024 Aug;142(4):108535
   

Investor Contact
Laura Hansen, Ph.D.
Vice President, Investor Relations
(650) 452-2747
hansen@dnli.com

Media Contact
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FGS Global
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rich.allan@fgsglobal.com

FAQ

What is the significance of FDA Breakthrough Therapy Designation for DNLI's tividenofusp alfa?

The designation expedites development and review, provides intensive FDA guidance, and indicates potential substantial improvement over existing therapies for Hunter syndrome.

When will Denali Therapeutics (DNLI) submit the BLA for tividenofusp alfa?

Denali plans to submit the Biologics License Application in early 2025 under the accelerated approval pathway.

What clinical evidence supports DNLI's tividenofusp alfa breakthrough designation?

The open-label Phase 1/2 study showed promising results with positive effects on surrogate endpoints and early signs of improved clinical outcomes in Hunter syndrome patients.

How many FDA designations does DNLI's tividenofusp alfa now have for Hunter syndrome?

Tividenofusp alfa has four FDA designations: Breakthrough Therapy, Fast Track, Orphan Drug, and Rare Pediatric Disease Designation.

What regulatory benefits does DNLI receive with the Breakthrough Therapy Designation?

The designation provides more intensive FDA guidance, senior reviewer involvement, and eligibility for rolling review and priority review of the marketing application.